One of the fields of application of the invention is related to the measurement of EBI in portable, wearable, and/or implantable medical devices and apparatuses for determining the conditions of organs and tissues, especially of transplantable and/or transplanted organs and tissues.
Biomedical Background
Tissue edema is, in general, a pathological change in liquid amount and balance in the tissue. Depending on their initial causes, the edemas are found to be of three types: cellular, extracellular (interstitial) and combined (see A. Kink, M. Min, T. Parve, I. Rätsep. Bioimpedance based analysis of tissue oedema. In: Proc. of the XII Internat. Conf. on Electrical Bioimpedance & the V Conf. on Electrical Impedance Tomography ICEBI/EIT 2004, Jun. 20-24, 2004, Gdansk, Poland, Vol. 1, pp. 29-32, incorporated herein by reference).
The cellular edema, which is known also as the ischemic or cytotoxic edema, occurs either through intracellular hyperosmolarity or through extracellular hypotonicity as a result of occlusion of the oxygen rich blood inflow or the arterial supply of tissue. The cellular edema results in swelling of cells due to sucking in the fluid from extracellular space.
The extracellular edema, known also as interstitial edema, is a result of buildup of fluids in extracellular space of the tissue (parenchyma). There are two ways for genesis of the extracellular edema:
a) the hydrostatic extracellular edema develops through increased ultrafiltration (leakage through the walls of capillars) or due to decreased reabsorption (inhibition of the venous outflow),
b) the oncotical extracellular edema is caused by shortage of proteins (swelling from starvation).
The combined edema includes both types of edema, cellular and extracellular, in some proportion. Both types of edema can be present together from the beginning of edema processes, but they can also develop successively depending on the initial cause (i.e., either the occlusion of arterial supply or venous outflow). As a rule, however, one type of edema causes the other to develop and vice versa in a mutually progressive way (called compartment syndrome).
Independently of the type or cause of the edema, the amount and balance of liquid in the tissue changes during edema which in turn can be monitored as changes in bioimpedance of the tissue (see S. Grimnes and Ø. G. Martinsen, Bioimpedance and Bioelectricity Basics, Academic Press, San Diego, 2000).
A developing cellular (ischemic) edema increases EBI of the tissue at lower frequencies, but the EBI decreases again after the blood circulation is restored. At higher frequencies the variations of impedance can be negligible. A permanently progressive edema can quickly lead to complete damage of the tissue through cell destruction. At this stage of edema, the impedance of the tissue at low frequencies decreases rapidly.
Engineering Background
PCT application WO 01/19426 “Implantable Device and Method for Long-Term Detection and Monitoring of Congestive Heart Failure” describes a measuring device, which is mounted into a pacemaker. Such device is used for observing complications developing in the cardiac blood vessel system and in the blood circulation in lungs. The method is based on directing various types of current/voltage excitation signals (rectangular waveform signal, sine wave signal, pulse signal, signal with varying frequency) through a bio-object and measuring the inphase and quadrature components of the electrical response to the excitation signal. The device measures variations in the impedance of the cardiac blood vessel system and of the blood circulation in lungs via measuring a current flow through the object, a voltage drop forming on it and a phase shift between the excitation and response signals. The described device enables this device to diagnose the interstitial edema in lungs.
The electrical bio-impedance (EBI) can give valuable information about both current condition of the tissue and changes in its conditions over a period of time.
PCT application WO 00/79255 “A method and device for Measuring Tissue Edema” suggests that presence of edema in a tissue can be diagnosed by measuring and comparing bioelectrical impedance of the tissue at a single low-frequency voltage at=two anatomical regions of a subject, one of the regions being unaffected by edema. For example, presence of edema in patient's right arm is determined by measuring the electric bio-impedance of the right arm and comparing it with the bio-impedance of the left arm. The frequency of the voltage according to one described method is 5 to 20 kHz, and preferably 10 kHz.
From the results of electrical impedance spectroscopy (see F. Thiel, G. Hahn, E. Gersing, T. Dudykevych, C. Hartung and G. Hellige, Semiparallel, multi-frequency equipment for electrical bio-impedance measurement, in Proc. of the XI Int. Conf. Electrical Bio-Impedance ICEBI2001, Jun. 17-21, 2001, Oslo, Norway, pp. 225-228; M. Osypka and E. Gersing. Parallel signal processing and multi-frequency EIT system, in Innov. Tech. Biol. Med., vol. 15, 1994, Special issue No. 1, pp. 56-61; M. Min, S. Ollmar, and E. Gersing, Electrical Impedance and Cardiac Monitoring—Technology, Potential and Applications, —Internat. Journal of Bioelectromagnetism, Vol. 5, 2003, No. 1, pp. 53-56; E. Gersing. Impedance spectroscopy on living tissue for determination of the state of organs, —Biochemistry and Bioenergetics, 45 (1998), pp. 145-149) it is possible to determine characteristic frequencies for a particular type of tissue, at which the analysis of electrical bio-impedance (EBI) can give the most valuable information about the tissue. At these frequencies the sharpest changes take place when the tissue is going through the different stages of edema. Selection of frequencies depends on the type of edema (cellular, interstitial, combined) and structure of tissue (myocardium, liver, brain, etc). For example, the study of canine liver (M. Gheorghiu, E. Gersing, E. Gheorghiu, On the quantitative evaluation of the time course of tissue impedance during ischemia, in Proc. of the XI Int. Conf. Electrical Bio-Impedance ICEBI2001, Jun. 17-21, 2001, Oslo, Norway, pp. 49-53) by wide range impedance spectroscopy showed that the low frequency should be chosen below 1 kHz, and the high frequency should be chosen above 10 kHz. For monitoring a muscle flap, the low frequency was chosen 170 Hz, intermediate frequency 10 kHz and high frequency 150 kHz (see A. Kink, et al, above).
Impedance spectroscopy gives good results in laboratory conditions (see e.g., E. Gersing. Impedance spectroscopy on living tissue for determination of the state of organs, —Biochemistry and Bioenergetics, 45 (1998), pp. 145-149), but cannot be used in wearable and implantable devices.
Theoretically, application of pure sine wave signals is presumed for determination of the complex impedance by its definition. Application of switching mode electronics operating with pulse signals (M. B. Howie, R. Dzonczyk, T. D. Sweeny. An evaluation of a new two-electrode myocardial electrical impedance monitor for detecting myocardial ischemia, Anesth Analg, 2001, 92, pp. 12-18) has been used frequently in low power devices, but misleading measurement errors appear due to uncertain impact of higher harmonics present in the pulse signals. For example, application of the simplest rectangular waveform pulses, most suitable for use in CMOS electronics, introduces serious measurement errors (see M. Min, and T. Parve, “Improvement of the vector analyser based on two-phase switching mode synchronous detection”, Measurement, Vol. 19 (1996), No. 2, pp. 103-111, incorporated herein by reference). However, these errors can be reduced substantially by methods and techniques described in PCT application PCT/EE03/00006 (published as WO2004/052198 on Jun. 30, 2004, and corresponding U.S. patent application Ser. No. 10/537,643, filed into national phase in the U.S. on Jun. 6, 2005, both applications incorporated herein by reference in their entirety).
In the solution described in the PCT application WO 00/79255 “A method and device for Measuring Tissue Edema” the EBI of the tissue is compared with the EBI of an analogical sample tissue. However, no such sample tissue is generally available, particularly in the case of a transplanted tissue. Furthermore, even if a sample is available on rare occasion, it is complicated to introduce and retain the electrodes in a sample tissue and in a tissue to be monitored identically, and therefore, indeterminacy occurs in comparing results from these tissues.
As wide range impedance spectroscopy is badly suitable for clinical practice, a method of edema monitoring using the EBI measurement at only some characteristic frequencies is taken under discussion, see U.S. Pat. No. 6,532,384 to Fukuda. This invention, however, is based on the simplest electrical model of a tissue, known as Cole-Cole model. In reality, the model of a tissue should be much more complicated. Therefore, Cole-Cole model leads to inaccurate choice of excitation frequencies. Methods based on Cole-Cole model comprise hardly quantifiable measurement errors, specifically when non-sinusoidal excitation signals must be used. Non-sinusoidal, i.e., pulse wave excitation signals are typical, e.g., for implantable devices (see PCT patent applications WO 2004/045406 and WO 2004/050178).